title: Genetic variants reducing MTR gene expression increase the risk of congenital heart disease in Han Chinese populations.
abstract: OBJECTIVE
  Elevated homocysteine levels are known to be a risk factor for congenital heart disease (CHD), but the mechanism underlying this effect is unknown. During early embryonic development, homocysteine removal is dictated exclusively by the MTR activity. To examine the role of MTR in CHD risk, we identified genetic variants in MTR and investigated the mechanisms that affect its expression levels and that increase the risk of CHD in Chinese populations.
  
  
  RESULTS
  The association between regulatory variants of the MTR gene and CHD was examined in three independent case-control studies in a total of 2340 patients with CHD and 2270 controls. The functional consequences of these variants were demonstrated using dual-luciferase assays, real-time polymerase chain reaction (PCR), electrophoretic mobility shift assays, surface plasma resonance, chromatin immunoprecipitation, and bisulfite sequencing, as well as by a group of predicted microRNAs using a gene reporter system. Two regulatory variants of MTR, -186T>G and +905G>A, were associated with an increased risk of CHD in both the separate and combined case-control studies (-186GG P = 1.32 × 10(-9); +905AA P = 6.35 × 10(-14)). Compared with the major allele, the -186G allele exhibited significantly lower promoter activity, decreased hnRNA and mRNA levels, reduced transcription factor binding affinity, and a more highly methylated promoter. The +905A allele exhibited a statistically stronger binding affinity to functional microRNAs that down regulate MTR expression at the translational level. Both of the minor alleles were correlated with elevated plasma homocysteine concentrations, indicating a genetic component for hyperhomocysteinaemia.
  
  
  CONCLUSIONS
  Regulatory variants of the MTR gene increase CHD risk by reducing MTR expression and inducing the homocysteine accumulation and elevation.
authors.affiliation: The State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
authors.forename: Jian-Yuan
authors.initials: JY
authors.lastname: Zhao
authors.forename: Bin
authors.initials: B
authors.lastname: Qiao
authors.forename: Wen-Yuan
authors.initials: WY
authors.lastname: Duan
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Gong
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Peng
authors.forename: Song-Shan
authors.initials: SS
authors.lastname: Jiang
authors.forename: Chen-Qi
authors.initials: CQ
authors.lastname: Lu
authors.forename: Yi-Jiang
authors.initials: YJ
authors.lastname: Chen
authors.forename: Hong-Bing
authors.initials: HB
authors.lastname: Shen
authors.forename: Guo-Ying
authors.initials: GY
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Wang
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D019175:DNA Methylation / Q000235:genetics; D005287:Ferredoxin-NADP Reductase / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics*; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D020138:Hyperhomocysteinemia / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics; D012307:Risk Factors; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D035683:MicroRNAs; D006710:Homocysteine; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; C585801:MTR protein, human
keywords: Congenital heart disease; Genetic variant; Homocysteine; Methionine synthase